Hydroxyurea

Trade Names:Droxia- Capsules 200 mg- Capsules 300 mg- Capsules 400 mg

Trade Names:Hydrea- Capsules 500 mg

Pharmacology

Inhibits DNA synthesis, interferes with conversion of ribonucleotides to deoxyribonucleotides, and may inhibit incorporation of thymidine into DNA.

Pharmacokinetics

Absorption

Hydroxyurea is rapidly absorbed. T _max is 1 to 4 h.

Distribution

Hydroxyurea distributes rapidly and widely in the body, and concentrates in leukocytes and erythrocytes. Vd approximates total body water.

Metabolism

Up to 60% of an oral dose undergoes metabolic conversion through pathways not fully characterized (eg, degradation by urease found in intestinal bacteria, saturable hepatic metabolism).

Elimination

Excretion is likely a linear first-order process. In patients with sickle cell anemia, the mean urinary recovery is about 40%.

Special Populations

Because renal excretion is a pathway of elimination for hydroxyurea, consider dosage reduction in patients with renal impairment. Closely monitor hematologic parameters.

No data are available supporting specific guidelines for dosage adjustment in patients with hepatic insufficiency. Closely monitor hematologic parameters.

Indications and Usage

Reduce frequency of painful crises and reduce need for blood transfusions in adult patients with sickle cell anemia with recurrent moderate to severe painful crises.

Tumor response has been demonstrated in melanoma; recurrent metastatic or inoperable carcinoma of the ovary; resistant chronic myelocytic leukemia (CML); in combination with irradiation therapy for local control of primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip.

Unlabeled Uses

Cervical carcinoma; polycythemia vera; essential thrombocytosis; HIV; thrombocythemia; psoriasis; in combination with radiation therapy as a radiation sensitizer in brain tumors, cervical cancer, and head and neck cancer.

Contraindications

Hypersensitivity to any component of the product. Marked bone marrow depression (ie, leukopenia [less than 2,500 WBC] or thrombocytopenia [less than 100,000]) or severe anemia ( Hydrea ).

Dosage and Administration

Base dosage on patient's actual or ideal weight, whichever is less.

PO

80 mg/kg as a single dose every third day, beginning at least 7 days before initiation of irradiation and continued during radiotherapy as well as indefinitely afterwards provided the patient is adequately observed and exhibits no unusual or severe reactions.

PO

A single-dose study suggests that in sickle cell anemia the initial dose should be reduced by 50% to a dose of 7.5 mg/kg daily.

PO Continuous therapy of 20 to 30 mg/kg as a single daily dose.

PO

15 mg/kg/day as a single dose. If blood cell counts are at acceptable levels, dosage may be increased by 5 mg/kg/day every 12 wk until max tolerated dose (highest dose not producing toxic blood cell counts over 24 consecutive wk), or 35 mg/kg/day, is reached. Dose is not increased if blood cell counts are between acceptable and toxic levels. If blood cell counts are considered toxic, discontinue hydroxyurea until hematologic recovery, then resume therapy after reducing dosage by 2.5 mg/kg/day from dose associated with hematologic toxicity. Then, titrate dose up or down every 12 wk in 2.5 mg/kg/day increments until patient is at a stable dose that does not result in hematologic toxicity for 24 wk. Any dose that produces hematologic toxicity twice should not be given again.

PO

80 mg/kg (2,000 to 3,000 mg/m ² ) as a single dose every third day.

PO 20 to 30 mg/kg as a single daily dose. Hold the dose if WBC decreases to less than 2,500/mm ³ or platelet count is less than 100,000/mm ³ .

General Advice

• Administer without regard to food, but administer in a consistent manner (either with or without food).
• Administer with food if GI upset occurs.
• If patient is unable to swallow capsules, the contents of the capsule can be emptied into a glass of water and swallowed immediately.
• Follow procedures for proper handling and disposal of anticancer drugs.
• If contents of capsule are spilled, wipe up immediately with a damp disposable towel and discard in a closed container, such as a plastic bag.
• Always wear impervious gloves when handling hydroxyurea, including bottles containing the product.

Storage/Stability

Store capsules at controlled room temperature (59° to 86°F) in a tightly closed container.

Drug Interactions

Hepatotoxicity, fatal hepatic failure, and severe neurotoxicity reported with concomitant use in HIV-positive patients.

Pancreatitis and hepatotoxicity have been reported.

Risk of bone marrow depression or other adverse events may be increased.

Hydroxyurea may increase serum uric acid levels.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Asthenia; convulsions; disorientation; dizziness; drowsiness (following large doses); hallucination; headache; malaise; severe peripheral neuropathy.

Dermatologic

Alopecia; atrophy of the skin and nails; black nail pigmentation; cutaneous vasculitic toxicities including gangrene and vasculitic ulcerations; dermatomyositis-like skin changes; facial erythema; hair loss; hyperpigmentation; maculopapular rash; peripheral erythema; scaling; skin cancer; skin rash; skin ulceration; violet papules.

GI

Anorexia; constipation; diarrhea; nausea; pancreatitis (fatal and nonfatal); stomatitis; vomiting.

Genitourinary

Abnormal bromsulphalein (BSP) retention; dysuria; temporary impairment of renal tubular function with elevated BUN, creatinine, and uric acid.

Hematologic-Lymphatic

Bleeding; low reticulocytes levels; low platelet levels; neutropenia.

Hepatic

Elevated hepatic enzymes; hepatotoxicity (fatal and nonfatal).

Metabolic-Nutritional

Weight gain.

Respiratory

Acute pulmonary reactions consisting of diffuse pulmonary infiltrates, dyspnea, and fever.

Miscellaneous

Fever; chills; edema; parvovirus B-19 infection.

Precautions

Pregnancy

Category D .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

May be more sensitive to the effects of hydroxyurea and may require a lower dosage regimen.

Renal Function

May temporarily impair renal tubular function accompanied by elevated serum uric acid, BUN, and creatinine levels. Use with caution; consider reducing the dose.

Bone marrow function

Because hydroxyurea is cytotoxic and myelosuppressive, do not administer if bone marrow function is markedly depressed.

Carcinogenesis

Hydroxyurea is presumed to be a human carcinogen.

Erythema

Patients who have received prior irradiation therapy may have an exacerbation of postirradiation erythema.

Erythrocytic abnormalities

Self-limiting megaloblastic erythropoiesis is often seen early in hydroxyurea therapy.

Overdosage

Symptoms

Acute mucocutaneous toxicity, edema of palms and soles followed by scales of hands and feet, severe generalized hyperpigmentation of the skin, soreness, stomatitis, violet erythema.

Patient Information

• Review dosing schedule with patient (every day or every third day).
• Advise patient that dose is individualized based upon condition being treated and size of the patient.
• Advise patient to take each dose either with or without food but to be consistent. Advise patient to take with food if stomach upset occurs.
• If patient is unable to swallow capsules, advise patient that the contents of the capsule can be emptied into a glass of water and swallowed immediately.
• Advise patient that if a dose is missed, take it as soon as possible. If close to the next dose, do not double the dose to catch up and take the next dose as scheduled.
• Advise patient to immediately report any of the following to health care provider: fever, chills, or other signs of infection; skin rash; sore throat, nausea, vomiting, or appetite loss; sores in the mouth or on the lips; unusual bruising or bleeding.
• Advise HIV-infected patient to report any of the following to health care provider: epigastric pain, nausea, vomiting, sweating, abdominal tenderness or distension, right upper abdominal pain, yellowing of the skin or eyes, dark urine.
• Advise patient that medication may cause drowsiness, constipation, redness of the face, skin rash, itching, and hair loss, and to notify health care provider if these occur and are bothersome or intolerable.
• Advise women of childbearing potential to use effective contraception during therapy.
• Advise patient that drug may cause drowsiness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.

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